Vertical transmission does not always lead to benign pathogen-host associations.

Understanding the capacity of pathogens to cause severe disease is of fundamental importance to human health and the preservation of biodiversity. Many of those pathogens are not only transmitted horizontally between unrelated hosts but also vertically between parents and their progeny. It is widely accepted that vertical transmission leads to the evolution of less virulent pathogens, but this idea stems from research that neglects the evolutionary response of hosts. Here, we use a game-theory model of coevolution between pathogen and host to show that vertical transmission does not always lead to more benign pathogens. We highlight scenarios in which vertical transmission results in pathogens exhibiting more virulence. However, we also predict that more benign outcomes are still possible (a) when generating new horizontal infections inflicts too much damage on hosts, (b) when clearing an infection is too costly for the host, and (c) when vertical transmission is promoted by a greater growth rate of the host population. Though our work offers a new perspective on the role of vertical transmission in pathogen-host systems, it does agree with previous experimental work.

Microchimerism as a source of information on future pregnancies.

Small numbers of fetal cells cross the placenta during pregnancy turning mothers into microchimeras. Fetal cells from all previous pregnancies accumulate forming the mother's fetal microchiome. What is significant about microchimeric cells is that they have been linked to health problems including reproductive and autoimmune diseases. Three decades after the discovery of fetal microchimerism, the function of these cells remains a mystery. Here, we contend that the role of microchimeric cells is to inform the fetus about the likelihood that its genes are present in future pregnancies. We argue that, when genes are more likely than average to be in future maternal siblings, fetuses will send a fixed number of cells that will not elicit a maternal immune response against them. However, when genes are less likely to be in future maternal siblings, fetuses will send an ever-increasing number of cells that will elicit an ever-stronger maternal immune response. Our work can explain the observed clinical association between microchimeric cells and pre-eclampsia. However, our work predicts that this association should be stronger in women with a genetically diverse microchiome. If supported by medical tests, our work would allow establishing the likelihood of pregnancy or autoimmune problems advising medical interventions.

Why do hybrids turn down sex?

Asexual reproduction is ancestral in prokaryotes; the switch to sexuality in eukaryotes is one of the major transitions in the history of life. The study of the maintenance of sex in eukaryotes has raised considerable interest for decades and is still one of evolutionary biology's most prominent question. The observation that many asexual species are of hybrid origin has led some to propose that asexuality in hybrids results from sexual processes being disturbed because of incompatibilities between the two parental species' genomes. However, in some cases, failure to produce asexual F1s in the lab may indicate that this mechanism is not the only road to asexuality in hybrid species. Here, we present a mathematical model and propose an alternative, adaptive route for the evolution of asexuality from previously sexual hybrids. Under some reproductive alterations, we show that asexuality can evolve to rescue hybrids' reproduction. Importantly, we highlight that when incompatibilities only affect the fusion of sperm and egg's genomes, the two traits that characterize asexuality, namely unreduced meiosis and the initiation of embryogenesis without the incorporation of the sperm's pronucleus, can evolve separately, greatly facilitating the overall evolutionary route. Taken together, our results provide an alternative, potentially complementary explanation for the link between asexuality and hybridization.

The Recombination Hotspot Paradox: Co-evolution between PRDM9 and its target sites.

Recombination often concentrates in small regions called recombination hotspots where recombination is much higher than the genome's average. In many vertebrates, including humans, gene PRDM9 specifies which DNA motifs will be the target for breaks that initiate recombination, ultimately determining the location of recombination hotspots. Because the sequence that breaks (allowing recombination) is converted into the sequence that does not break (preventing recombination), the latter sequence is over-transmitted to future generations and recombination hotspots are self-destructive. Given their self-destructive nature, recombination hotspots should eventually become extinct in genomes where they are found. While empirical evidence shows that individual hotspots do become inactive over time (die), hotspots are abundant in many vertebrates: a contradiction called the Recombination Hotspot Paradox. What saves recombination hotspots from their foretold extinction? Here we formulate a co-evolutionary model of the interaction among sequence-specific gene conversion, fertility selection, and recurrent mutation. We find that allelic frequencies oscillate leading to stable limit cycles. From a biological perspective this means that when fertility selection is weaker than gene conversion, it cannot stop individual hotspots from dying but can save them from extinction by driving their re-activation (resuscitation). In our model, mutation balances death and resuscitation of hotspots, thus maintaining their number over evolutionary time. Interestingly, we find that multiple alleles result in oscillations that are chaotic and multiple targets in oscillations that are asynchronous between targets thus helping to maintain the average genomic recombination probability constant. Furthermore, we find that the level of expression of PRDM9 should control for the fraction of targets that are hotspots and the overall temperature of the genome. Therefore, our co-evolutionary model improves our understanding of how hotspots may be replaced, thus contributing to solve the Recombination Hotspot Paradox. From a more applied perspective our work provides testable predictions regarding the relation between mutation probability and fertility selection with life expectancy of hotspots.

On maternity and the stronger immune response in women.

Medical research reports that women often exhibit stronger immune responses than men, while pathogens tend to be more virulent in men. Current explanations cannot account for this pattern, creating an obstacle for our understanding of infectious-disease outcomes and the incidence of autoimmune diseases. We offer an alternative explanation that relies on a fundamental difference between the sexes: maternity and the opportunities it creates for transmission of pathogens from mother to child (vertical transmission). Our explanation relies on a mathematical model of the co-evolution of host immunocompetence and pathogen virulence. Here, we show that when there is sufficient vertical transmission co-evolution leads women to defend strongly against temperate pathogens and men to defend weakly against aggressive pathogens, in keeping with medical observations. From a more applied perspective, we argue that limiting vertical transmission of infections would alleviate the disproportionate incidence of autoimmune diseases in women over evolutionary time.

Epigenetic memories and the evolution of infectious diseases.

Genes with identical DNA sequence may show differential expression because of epigenetic marks. Where epigenetic marks respond to past conditions, they represent a form of "memory". Despite their medical relevance, the impact of memories on the evolution of infectious diseases has rarely been considered. Here we explore the evolution of virulence in pathogens that carry memories of the sex of their previous host. We show that this form of memory provides information about the sex of present and future hosts when the sexes differ in their pathogen's transmission pattern. Memories of past hosts enable the evolution of greater virulence in infections originating from one sex and infections transmitted across sexes. Thus, our results account for patterns of virulence that have, to date, defied medical explanation. In particular, it has been observed that girls infected by boys (or boys infected by girls) are more likely to die from measles, chickenpox and polio than girls infected by girls (or boys infected by boys). We also evaluate epigenetic therapies that tamper with the memories of infecting pathogens. More broadly, our findings imply that pathogens can be selected to carry memories of past environments other than sex. This identifies new directions in personalised medicine.

Stable cycling in quasi-linkage equilibrium: Fluctuating dynamics under gene conversion and selection.

Genetic systems with multiple loci can have complex dynamics. For example, mean fitness need not always increase and stable cycling is possible. Here, we study the dynamics of a genetic system inspired by the molecular biology of recognition-dependent double strand breaks and repair as it happens in recombination hotspots. The model shows slow-fast dynamics in which the system converges to the quasi-linkage equilibrium (QLE) manifold. On this manifold, sustained cycling is possible as the dynamics approach a heteroclinic cycle, in which allele frequencies alternate between near extinction and near fixation. We find a closed-form approximation for the QLE manifold and use it to simplify the model. For the simplified model, we can analytically calculate the stability of the heteroclinic cycle. In the discrete-time model the cycle is always stable; in a continuous-time approximation, the cycle is always unstable. This demonstrates that complex dynamics are possible under quasi-linkage equilibrium.

PRDM9 and the evolution of recombination hotspots.

Recombination in mammals is not uniformly distributed along the chromosome but concentrated in small regions known as recombination hotspots. Recombination starts with the double-strand break of a chromosomal sequence and results in the transmission of the sequence that does not break (preventing recombination) more often than the sequence that breaks (allowing recombination). Thus recombination itself renders individual recombination hotspots inactive and over time should drive them to extinction in the genome. Empirical evidence shows that individual recombination hotspots die but, far from being driven to extinction, they are abundant in the genome: a contradiction referred to as the Recombination Hotspot Paradox. What saves recombination hotspots from extinction? The current answer relies in the formation of new recombination hotspots in new genomic sites driven by viability selection in favor of recombination. Here we formulate a population genetics model that incorporates the molecular mechanism initiating recombination in mammals (PRDM9-like genes), to provide an alternative solution to the paradox. We find that weak selection allows individual recombination hotspots to become inactive (die) while saving them from extinction in the genome by driving their re-activation (resurrection). Our model shows that when selection for recombination is weak, the introduction of rare variants causes recombination sites to oscillate between hot and cold phenotypes with a recombination hotspot dying only to come back. Counter-intuitively, we find that low viability selection leaves a hard selective sweep signature in the genome, with the selective sweep at the recombination hotspot being the hardest when viability selection is the lowest. Our model can help to understand the rapid evolution of PRDM9, the co-existence of two types of hotspots, the life expectancy of hotspots, and the volatility of the recombinational landscape (with hotspots rarely being shared between closely related species).

The meaning of intragenomic conflict.

Recent years have seen an explosion of interest in genes that function for their own good and to the detriment of other genes that reside in the same genome. Such intragenomic conflicts are increasingly recognized to underpin maladaptation and disease. However, progress has been impeded by a lack of clear understanding regarding what intragenomic conflict actually means, and an associated obscurity concerning its fundamental drivers. Here we develop a general theory of intragenomic conflict in which genes are viewed as inclusive-fitness-maximizing agents that come into conflict when their inclusive-fitness interests disagree. This yields a classification of all intragenomic conflicts into three categories according to whether genes disagree about where they have come from, where they are going, or where they currently are. We illustrate each of these three basic categories, survey and classify all known forms of intragenomic conflict, and discuss the implications for organismal maladaptation and human disease.

The evolution of sex-specific virulence in infectious diseases.

Fatality rates of infectious diseases are often higher in men than women. Although this difference is often attributed to a stronger immune response in women, we show that differences in the transmission routes that the sexes provide can result in evolution favouring pathogens with sex-specific virulence. Because women can transmit pathogens during pregnancy, birth or breast-feeding, pathogens adapt, evolving lower virulence in women. This can resolve the long-standing puzzle on progression from Human T-cell Lymphotropic Virus Type 1 (HTLV-1) infection to lethal Adult T-cell Leukaemia (ATL); a progression that is more likely in Japanese men than women, while it is equally likely in Caribbean women and men. We argue that breastfeeding, being more prolonged in Japan than in the Caribbean, may have driven the difference in virulence between the two populations. Our finding signifies the importance of investigating the differences in genetic expression profile of pathogens in males and females.

The evolving landscape of imprinted genes in humans and mice: Conflict among alleles, genes, tissues, and kin.

Three recent genome-wide studies in mice and humans have produced the most definitive map to date of genomic imprinting (gene expression that depends on parental origin) by incorporating multiple tissue types and developmental stages. Here, we explore the results of these studies in light of the kinship theory of genomic imprinting, which predicts that imprinting evolves due to differential genetic relatedness between maternal and paternal relatives. The studies produce a list of imprinted genes with around 120-180 in mice and ~100 in humans. The studies agree on broad patterns across mice and humans including the complex patterns of imprinted expression at loci like Igf2 and Grb10. We discuss how the kinship theory provides a powerful framework for hypotheses that can explain these patterns. Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression.

Intragenomic Conflict over Dispersal.

Intragenomic conflict may arise when social partners are more related through one parent than the other-for example, owing to individuals or gametes of one sex dispersing further prior to fertilization. In particular, genes originating from the former parent are favored to promote selflessness, and those originating from the latter parent are favored to promote selfishness. While the impact of patterns of dispersal on the evolution of intragenomic conflict has received recent attention, the consequences of intragenomic conflict for the evolution of dispersal remain to be explored. We suggest that if the evolution of dispersal is driven at least in part by kin selection, differential relatedness of social partners via their mothers versus their fathers may lead to an intragenomic conflict, with maternal-origin genes and paternal-origin genes favoring different rates of dispersal. As an illustration, we extend a classic model of the evolution of dispersal to explore how intragenomic conflict may arise between an individual's maternal-origin and paternal-origin genes over whether that individual should disperse in order to ease kin competition. Our analysis reveals extensive potential for intragenomic conflict over dispersal and predicts that genes underpinning dispersal phenotypes may exhibit parent-of-origin-specific expression, which may facilitate their discovery.

Mother and offspring in conflict: why not?

A gene mediating interactions between mouse mothers and their pups has recently been claimed to support coadaptation rather than the kinship theory of genomic imprinting. This Formal Comment argues that this claim is unfounded.

On the origin of sex chromosomes from meiotic drive.

Most animals and many plants make use of specialized chromosomes (sex chromosomes) to determine an individual's sex. Best known are the XY and ZW sex-determination systems. Despite having evolved numerous times, sex chromosomes present something of an evolutionary puzzle. At their origin, alleles that dictate development as one sex or the other (primitive sex chromosomes) face a selective penalty, as they will be found more often in the more abundant sex. How is it possible that primitive sex chromosomes overcome this disadvantage? Any theory for the origin of sex chromosomes must identify the benefit that outweighs this cost and enables a sex-determining mutation to establish in the population. Here we show that a new sex-determining allele succeeds when linked to a sex-specific meiotic driver. The new sex-determining allele benefits from confining the driving allele to the sex in which it gains the benefit of drive. Our model requires few special assumptions and is sufficiently general to apply to the evolution of sex chromosomes in outbreeding cosexual or dioecious species. We highlight predictions of the model that can discriminate between this and previous theories of sex-chromosome origins.

Specialists and generalists: the sexual ecology of the genome.

Sexual antagonism occurs when an allele is beneficial in one sex but costly in the other. Parental antagonism occurs when an allele is beneficial when inherited from one sex but costly when inherited from the other because of fitness interactions among kin. Sexual and parental antagonisms together define four genetic niches within the genome that favor different patterns of gene expression. Natural selection generates linkage disequilibrium among sexually and parentally antagonistic loci with male-beneficial alleles coupled to alleles that are beneficial when inherited from males and female-beneficial alleles coupled to alleles that are beneficial when inherited from females. Linkage disequilibrium also develops between sexually and parentally antagonistic loci and loci that influence sex determination. Genes evolve sex-specific expression to resolve sexual antagonism and evolve imprinted expression to resolve parental antagonism. Sex-specific chromosomes allow a gene to specialize in a single niche.

First principles of Hamiltonian medicine.

We introduce the field of Hamiltonian medicine, which centres on the roles of genetic relatedness in human health and disease. Hamiltonian medicine represents the application of basic social-evolution theory, for interactions involving kinship, to core issues in medicine such as pathogens, cancer, optimal growth and mental illness. It encompasses three domains, which involve conflict and cooperation between: (i) microbes or cancer cells, within humans, (ii) genes expressed in humans, (iii) human individuals. A set of six core principles, based on these domains and their interfaces, serves to conceptually organize the field, and contextualize illustrative examples. The primary usefulness of Hamiltonian medicine is that, like Darwinian medicine more generally, it provides novel insights into what data will be productive to collect, to address important clinical and public health problems. Our synthesis of this nascent field is intended predominantly for evolutionary and behavioural biologists who aspire to address questions directly relevant to human health and disease.

Ecology drives intragenomic conflict over menopause.

Menopause is the transition from reproductive to non-reproductive life well before natural death. Rather than involving a smooth, rapid change, it is normally preceded by a long period of erratic hormonal fluctuation that is accompanied by a plethora of unpleasant symptoms. Here, we (1) suggest that this turbulent period owes to conflict, between a woman's maternally inherited (MI) and paternally inherited (PI) genes, over the trade-off between reproduction and communal care; (2) perform a theoretical analysis to show that this conflict is resolved either through silencing or fluctuating expression of one of the genes; (3) highlight which of the symptoms preceding menopause may result from antagonistic co-evolution of MI and PI genes; (4) argue that ecological differences between ancestral human populations may explain the variability in menopause among different ethnic groups; (5) discuss how these insights may be used to inform family planning and cancer risk assessment based on a woman's ancestral background.

Sexual and parental antagonism shape genomic architecture.

Populations with two sexes are vulnerable to a pair of genetic conflicts: sexual antagonism that can arise when alleles have opposing fitness effects on females and males; and parental antagonism that arises when alleles have opposing fitness effects when maternally and paternally inherited. This paper extends previous theoretical work that found stable linkage disequilibrium (LD) between sexually antagonistic loci. We find that LD is also generated between parentally antagonistic loci, and between sexually and parentally antagonistic loci, without any requirement of epistasis. We contend that the LD in these models arises from the admixture of gene pools subject to different selective histories. We also find that polymorphism maintained by parental antagonism at one locus expands the opportunity for polymorphism at a linked locus experiencing parental or sexual antagonism. Taken together, our results predict the chromosomal clustering of loci that segregate for sexually and parentally antagonistic alleles. Thus, genetic conflict may play a role in the evolution of genomic architecture.

Comentarios del Comité Español Interdisciplinario de Prevención Cardiovascular (CEIPC) a las Guías Europeas de Prevención Cardiovascular 2012 / Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC for its Spanish acronym) on the 2012 European Cardiovascular Prevention Guidelines

Las guías europeas de prevención cardiovascular contemplan 2 sistemas de evaluación de la evidencia (SEC y GRADE) y recomiendan combinar las estrategias poblacional y de alto riesgo, interviniendo en todas las etapas de la vida, con la dieta como piedra angular de la prevención. La valoración del riesgo cardiovascular (RCV) incorpora los niveles de HDL y los factores psicosociales, una categoría de muy alto riesgo y el concepto edad-riesgo. Se recomienda el uso de métodos cognitivo-conductuales (entrevista motivadora, intervenciones psicológicas), aplicados por profesionales sanitarios, con la participación de familiares de los pacientes, para contrarrestar el estrés psicosocial y reducir el RCV mediante dietas saludables, entrenamiento físico, abandono del tabaco y cumplimiento terapéutico. También se requieren medidas de salud pública, como la prohibición de fumar en lugares públicos o eliminar los ácidos grasos trans de la cadena alimentaria. Otras novedades consisten en desestimar el tratamiento antiagregante en prevención primaria y la recomendación de mantener la presión arterial dentro del rango 130-139/80-85 mmHg en pacientes diabéticos o con RCV alto. Se destaca el bajo cumplimiento terapéutico observado, porque influye en el pronóstico de los pacientes y en los costes sanitarios. Para mejorar la prevención cardiovascular se precisa una verdadera alianza entre políticos, administraciones, asociaciones científicas y profesionales de la salud, fundaciones de salud, asociaciones de consumidores, pacientes y sus familias, que impulse la estrategia tanto poblacional como individual mediante el uso de toda la evidencia científica disponible, desde ensayos clínicos hasta estudios observacionales y modelos matemáticos para evaluar intervenciones a nivel poblacional, incluyendo análisis de coste-efectividad

Based on the two main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions - such as smoking ban in public areas or the elimination of trans fatty acids from the food chain - are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses

Comentarios del Comité Español Interdisciplinario de Prevención Cardiovascular (CEIPC) a las Guías Europeas de Prevención Cardiovascular 2012 / Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC for its Spanish acronym) on the 2012 European Cardiovascular Prevention Guidelines

Las guías europeas de prevención cardiovascular contemplan 2 sistemas de evaluación de la evidencia (SEC y GRADE) y recomiendan combinar las estrategias poblacional y de alto riesgo, interviniendo en todas las etapas de la vida, con la dieta como piedra angular de la prevención. La valoración del riesgo cardiovascular (RCV) incorpora los niveles de HDL y los factores psicosociales, una categoría de muy alto riesgo y el concepto edad-riesgo. Se recomienda el uso de métodos cognitivo-conductuales (entrevista motivadora, intervenciones psicológicas), aplicados por profesionales sanitarios, con la participación de familiares de los pacientes, para contrarrestar el estrés psicosocial y reducir el RCV mediante dietas saludables, entrenamiento físico, abandono del tabaco y cumplimiento terapéutico. También se requieren medidas de salud pública, como la prohibición de fumar en lugares públicos o eliminar los ácidos grasos trans de la cadena alimentaria. Otras novedades consisten en desestimar el tratamiento antiagregante en prevención primaria y la recomendación de mantener la presión arterial dentro del rango 130-139/80-85 mmHg en pacientes diabéticos o con RCV alto. Se destaca el bajo cumplimiento terapéutico observado, porque influye en el pronóstico de los pacientes y en los costes sanitarios. Para mejorar la prevención cardiovascular se precisa una verdadera alianza entre políticos, administraciones, asociaciones científicas y profesionales de la salud, fundaciones de salud, asociaciones de consumidores, pacientes y sus familias, que impulse la estrategia tanto poblacional como individual mediante el uso de toda la evidencia científica disponible, desde ensayos clínicos hasta estudios observacionales y modelos matemáticos para evaluar intervenciones a nivel poblacional, incluyendo análisis de coste-efectividad (AU)

Based on the two main frameworks for evaluating scientific evidence-SEC and GRADE-European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions, led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions-such as smoking ban in public areas or the elimination of trans fatty acids from the food chain-are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure (BP) within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses